Synthesis and biological evaluation of 1-(4′-Indolyl and 6′-Quinolinyl) indoles as a new class of potent anticancer agents

A novel series of the biheterocycles-based compounds with core structure distinguished from combretastatin A-4 (1) and colchicine (5) have been synthesized and evaluated as potent anti-mitotic agents. Compound 1-(4′-Indolyl and 6′-quinolinyl)-4,5,6-trimethoxyindoles 13 and 19 showed substantial anti-proliferative activity against various human cancer cell lines, regardless to the tissue origin and the expression of multiple-drug resistance MDR1, with a mean IC50 value of 38 and 24 nM respectively. Compound 13 (IC50 = 1.7 μM) also exhibited similar anti-tubulin activities to 1 (IC50 = 1.8 μM) and displayed strong binding property to the colchicine binding site on the microtubules. Computational modeling analysis revealed that the binding mechanism of compound 13 is similar to that of CA4.

Graphical abstractA novel series of biheterocycles-based compounds, 1-(heteroaryl)-4,5,6-trimethoxyindoles, exhibits substantial microtubule destabilizing activity through interference with the colchicine binding site of the microtubule.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 1-(4′-Indolyl and 6′-quinolinyl)indoles as potent anti-mitotic agents. ► Rational design from natural product (cis-stilbene) to afford the biheterocycles. ► Application of copper-mediated 1-arylation of indole.